EUCAST Révolution ou changement - Infectiologie...Structure. § Ceftolozane/tazobactam is a novel 3′-aminopyrazolium cephalosporin and β-lactamase inhibitor combination being developed

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1

EUCAST

Révolution ou changement ? Impact en clinique

L. Dubreuil Faculté de Pharmacie Lille

Service des Maladies infectieuses Tourcoing

Déclaration conflits d’intérêt

•  Nom prénom Dubreuil Luc •  Fonction…PU-PH •  Conflits d’intérêt

Contrats de recherche sur antibiotiques: –  Fleurir USA –  Sylveos

Congrès SFM 2014 CASFM – EUCAST – Session DPC – 01/04/2014

The Shape of Cures to Come™ Cubist Pharmaceuticals

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Ceftolozane/tazobactam = Zerbaxa 1.5 g q8h ou 3 g q8h

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CEFTOLOZANE/TAZOBACTAM Structure

§  Ceftolozane/tazobactam is a novel 3′-aminopyrazolium cephalosporin and β-lactamase inhibitor combination being developed as a 2:1 ratio for treatment of serious Gram-negative bacterial infections

N

S

CO2H

NOHN

NO

H HO

CO2HH3C

N

S N

H2N

NCH3

NH2

HNO

HNNH2

CH3

HSO4-

+

N

S

O

H OO

NN

N

OHO

+

Ceftolozane Tazobactam

4 Previous names: CXA-101, CXA-201, FR264205

5

The Efficacy of Ceftolozane Correlates Best With %Time > MIC (%T>MIC) = Zerbaxa®

n  Neutropenic mouse thigh infection model used to establish ceftolozane parameters1

n  %T>MIC is the PK/PD measure most correlated with the in vivo efficacy of ceftolozane

5 Craig and Andes. Antimicrob Agents Chemother. 2013;57:1577-82.

•  R2 represents the percentage of variance in colony forming unit (CFU)/thigh that can be attributed to each PK/PD index. AUC, area under the curve; MIC, minimum inhibitory concentration. Organism used: Klebsiella pneumoniae

10

5

Log 1

0 CFU

/thig

h at

24

h

6

7

8

9

10

4

3 100 1000 1

Cmax/MIC 10 100 1000

24-h AUC/MIC 0 20 40 60 80

Time>MIC

R2 = 45.9% R2 = 61.0% R2 = 20.0%

For Internal Training Purposes Only

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In vitro PD model: Ceftolozane

Data on file Cubist CXA.040.MC

Relationship between fT>MIC and log reduction in 24 hr viable counts

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Summary Pharmacodynamic Ceftolozane Targets

n  Stasis %T > MIC target of < 30% derived from neutropenic mouse thigh models for ceftolozane was lower than other cephalosporins

n  %T>MIC does not change based on MIC

%T>MIC, percentage of time that the drug concentration exceeds minimum inhibitory concentration; ESBL, extended spectrum β-lactamase. 1. Lepak et al. Antimicrob Agents Chemother. 2014;58(10):6311-63142. Craig and Andes. Antimicrob Agents Chemother. 2013;57:1577-82. 7

Mean Stasis %T>MIC

1-log kill %T>MIC

2-log kill %T>MIC

S. pneumoniae1 18.1 23.8 26.7

P. aeruginosa1 31.2 39.4 42.0

Enterobacteriaceae (wild-type)2 26.3 31.6 NA

Enterobacteriaceae (ESBL producers)2 31.1 34.8 NA

§  Population PK parameters from the analysis were input into Pharsight Clinical Trial Simulator

§  1000 subjects were simulated

§  Dosing regimen =1000 mg ceftolozane Q8h as a 1-hr infusion

§  Intensive plasma sampling simulated on Day 7

§  Target attainment rates were determined for MICs ranging from 0.5-64 mg/L

CEFTOLOZANE/TAZOBACTAM Monte Carlo Simulations

Probability of target attainment by MIC

MIC (mg/L) 30% T>MIC (%)

0.5 100

1 99.8

2 99

4 97.5

8 90.1

16 67.8

32 30

64 3.4

8

9

Probability of Target Attainment Against P. aeruginosa 1.0-g CEFTOLOZANE dose = Zerbaxa®

n  PTA is ≥ 94.7% for the 1 log10 kill target against Pseudomonas with an MIC value up to 8 mg/L in plasma for the 1 g ceftolozane dose

9 Melhem et al. ECCMID. 2014. Poster P1743. For Internal Training Purposes Only

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Simulated Target Attainment Data

§  Thus a dose of 2000mg CAZ/500mg NXL104 given as a 2h infusion is intended for Phase 3

*CT=1

CAZ MIC (µg/ml)

500mg CAZ/125mg NXL104 30-min infusion (Phase 2 cUTI dose) 50% T>MIC & T>*CT

2000mg CAZ/500mg NXL104 30-min infusion (Phase 2 cIAI dose) 50% T>MIC & T>*CT

2000mg CAZ/500mg NXL104 2-h infusion (Proposed Phase 3 dose) 50% T>MIC & T>*CT

0.125 55.6 86.3 96.1 0.25 55.6 86.3 96.1 0.5 55.6 86.3 96.1 1 55.4 86.3 96.1 2 51.9 86.3 96.1 4 31.8 86 96 8 5 78.8 92.1

16 0 41.9 57.1 32 0 5.9 8.6

Zavicefta

11

Target attainment for patients with cSSTI with PK/PD target defined by the median value of the pre-clinical in murine thigh infection model

Target attainment simulations

S. aureus 26% T>MIC (bacterial stasis) supports a PK/PD target of 2 mg/L

PK/PD target based on pre-clinical studies

12

Organism (N)

%T>MIC

Stasis 1 log kill 2 log kill

Staphylococcus aureus (N=4) 26 (15-36) 35 (18-44) 51 (23-56)

Streptococcus pneumoniae (N=5) 35 (29-52) 44 (33-59) 51 (36-64)

Enterobacteriaceae* (N=5) 32 (15-37) 44 (24-57) 53 (50-58)+

Median (min-max range) of the PK/PD target based on in vivo efficacy of Ceftaroline in the murine thigh and lung* infection models

Study P0903-M-003 (2004); Andes and Craig, (2006) AAC 50: 1376-1383

+ N=3

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Target attainment for patients with cSSTI with PK/PD target defined by the median value of the pre-clinical in murine thigh infection model

Target attainment simulations

S. aureus 26% T>MIC (bacterial stasis) supports a PK/PD target of 2 mg/L

Coagulase-negative staphylococci

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Norfloxacin 10-ug disk vs MICS. aureus , 101 clinical isolates

0

5

10

15

20

25

30

35

6 8 10 12 14 16 18 20 22 24 26 28 30

Inhibition zone diameter (mm)

No o

f iso

late

s

>6464321684210.5<0.25

Breakpoints ECOFF MIC (screen) 4 mg/L Zone diameter 17/17

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Rifampicin 5-ug disk vs MICS. aureus , 166 clinical isolates

0

5

10

15

20

25

30

35

6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40


No o

f iso

late

s

>44210.50.250.120.060.030.0150.0080.004

Breakpoints ECOFF MIC 0.06/0.5 0.016 mg/L Zone diameter 25/22

0

5

10

15

20

25

30

35

6 8 10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

42

44

46

48

50

No

of is

olat

es


Ciprofloxacin 5 µg vs. MIC Pseudomonas aeruginosa, 164 clinical isolates

≥8

4

2

1

0.5

0.25

0.12

≤0.06

Breakpoints ECOFF MIC S≤0.5, R>1 mg/L WT≤0.5 mg/L Zone diameter S≥25, R<22 mm

MIC (mg/L)

0

2

4

6

8

10

12

14

16

18

6 8 10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

42

44

46

48

50

No

of is

olat

es


Ciprofloxacin 5 µg vs. MIC Pseudomonas non-aeruginosa, 173 clinical isolates

≥8

4

2

1

0.5

0.25

0.12

0.06

≤0.03

MIC (mg/L)

Breakpoints ECOFF MIC S≤0.5, R>1 mg/L WT≤0.5 mg/L Zone diameter S≥25, R<22 mm

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Détermination de la Sensibilité aux Antibiotiques

Méthode de diffusion de l’EUCAST en gélose

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Milieux en fonction des bactéries Organismes Milieu Enterobactéries Pseudomonas spp. Stenotrophomonas maltophilia Acinetobacter spp. Staphylococcus spp. Enterococcus spp.

Gélose de Mueller-Hinton

Streptococcus pneumoniae Streptococcus des groupes A, B, C et G Streptocoques du groupe viridans Haemophilus spp. Moraxella catarrhalis Listeria monocytogenes Pasteurella multocida Campylobacter jejuni et C. coli

Gélose de Mueller-Hinton + 5% de sang de cheval défibriné + 20 mg/L β-NAD (MH-F)

Autres bactéries à croissance lente Selon

S. pneumoniae ATCC 49619 H. influenzae NCTC 8468

MH + 5% defibrinated horse blood and 20 mg/L β-NAD Grows streptococci and H. influenzae

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Inoculum

•  La méthode nécessite d’obtenir un inoculum dont la turbidité est identique à l’étalon 0,5 de la gamme de McFarland*.

* Pour E. coli. cela correspond approximativement à 1-2 x108 UFC/mL

EUCAST 2013 Version 3.0 23

Inoculation des boîtes de Petri •  L’inoculum doit être employé de façon optimale dans un

délai de 15 minutes sans jamais dépasser une heure.

•  Plonger l’écouvillon en coton dans la suspension bactérienne et jeter l’excès en tournant l’écouvillon à l’intérieur du tube.

•  Etaler sur toute la surface en ensemençant dans trois directions soit à l’aide d’un système rotatif.

24

Dépôt des disques •  Le dépôt des disques doit être réalisé

dans les 15 minutes qui suivent l’inoculation

•  Les disques doivent être en contact ferme avec la surface de la gélose.

•  La disposition des disques devra être telle que les zones d’inhibition des souches sensibles ne se superposent pas et pour éviter toute interférence entre les antibiotiques; il est important que la mesure des diamètres d’inhibition soit fiable.

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La culture devra être confluente et uniformément répartie sur la surface de

la gélose.

Ce que l’on devrait atteindre.. ..et ce que l’on ne doit pas obtenir !

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Souches du contrôle de qualité EUCAST pour la routine

Organisme

Référence dans les collections Caractéristiques de la souche

E. coli ATCC 25922; NCTC 12241; CIP 7624 DSM 1103; CCUG 17620, CECT 434

Sensible, sauvage

P. aeruginosa ATCC 27853; NCTC 12903; CIP 76110 DSM 1117; CCUG 17619; CECT 108

Sensible, sauvage

S. aureus ATCC 29213; NCTC 12973; CIP 103429 DSM 2569; CCUG 15915; CECT 794

Faible production de β-lactamase

E. faecalis ATCC 29212; NCTC 12697; CIP 103214 DSM 2570; CCUG 9997; CECT 795

Sensible, sauvage

S. pneumoniae ATCC 49619; NCTC 12977; CIP 104340 DSM 11967; CCUG 33638

Intermédiaire à la Pénicilline G

H. influenzae NCTC 8468; CIP5494, CCUG 23946 Sensible, sauvage

Campylobacter jejuni

ATCC 33560; NCTC 11351; CIP 702 DSM 4688; CCUG 11284

Sensible, sauvage

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Souches EUCAST pour la détection de mécanismes de résistance

Organisme Référence dans les collections Caractéristiques de la souche

E. coli ATCC 35218; NCTC 11954;

CIP 102181; DSM 5564; CCUG 30600; CECT 943

β-lactamase TEM-1

K. pneumoniae ATCC 700603; NCTC 13368; CCUG 45421; CECT 7787 BLSE (SHV-18)

S. aureus NCTC 12493 Hétérorésistante à l’oxacilline, (mecA )

E. faecalis ATCC 51922; NCTC 13379;

CIP 104676; DSM 12956 CCUG 34289

Résistance à haut niveau aux aminosides et résistante à la vancomycine (vanB )

H. influenzae ATCC 49247; NCTC 12699;

CIP 104604; DSM 9999; CCUG 26214

Résistance à l’ampicilline (BLNAR) sans production de ß-lactamase

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Intermédiaire Pas de I si une seule posologie Cetazidime et céfépime 8 mg/L pyocyanique Moxifloxacine

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0.125 0.25 0.5 1 2 4 8 16 320

20

40

60

80

100

99% percentileMean

imipenem 1000 mg x 3 iv

95% percentile

MIC mg/L

%fT

>MIC

0.125 0.25 0.5 1 2 4 8 16 320

20

40

60

80

100

99% percentile

Mean

imipenem 500 mg x 4 iv

95% percentile

MIC mg/L

%fT

>MIC

Monte Carlo simulations of imipenem 1000 mg x 3 iv and 500 mg x 4 iv

2 2

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Etudetrans-réseauxONERBA2011-2012

An(biogrammestandardNSàuncarbapénème(erta/CMI)

Tic+Clavulanate<15mm

Méropénème<22mmou

Imipénème<22mm

Témocilline<15mm

NON OUI

NON

OUI

Souchessanscarbapénèmase

NON

RICAI 2014Disquesde6mm–Témocilline30µgGéloseMueller-Hinton(MH)etMHcloxacilline250mg/l

Gpes1&2Testcomplémentaire(BM?)

Gpes1&2

Se=100%-Sp=60%Tests:96/171=56%47/96carbase+=49%

sanstestcloxa

MH Nicolas


An(biogrammestandardNSàuncarbapénème



Imipénème<22mm

Témocilline<15mm

NON OUI

NONOUI

OUI


NON

RICAI 2014 Disquesde6mm–Témocilline30µgGéloseMueller-Hinton(MH)etMHcloxacilline250mg/l

Céfépime<26mm

Gpes1&2&3Testcomplémentaire(BM?)

Gpes1&2

Gpe3

Gpe3

OUI


NON

Se=100%-Sp=69%Tests145/349=41,5%52/145carbapse+=36%

sanstestcloxa

Gpes 1 & 2 & 3

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An(biogrammestandardNSàuncarbapénème



Imipénème<22mm

Témocilline<15mm

NON OUI

NONOUI

OUI


NON

Disquesde6mm–Témocilline30µgGéloseMueller-Hinton(MH)etMHcloxacilline250mg/l

Céfépime<26mm&

MéropénèmeMH-Cloxa<32mm

Gpes1&2&3Testcomplémentaire(BM?)

Gpes1&2

Gpe3

Gpe3

OUI


NON

Se=100%-Spe=79%Tests:115/349=33%52/115carbase+=45%

avectestcloxa

RICAI 2014

Gpes 1 & 2 & 3

0

10

20

30

40

50

60

6 8 10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

No

of is

olat

es


Temocillin 30 µg (Oxoid disks) Enterobacteriaceae, 195 clinical isolates

OXA-48

OXA-181

VIM

NDM-1

KPC

AmpC

ESBL

WT

Activity of NXL104 ( a new ß-lactamase

inhibitor) in Combination with ß-lactams

L. J. DUBREUIL1, S. MAHIEUX 1, C. NEUT 1, C. MIOSSEC 2, J. PACE 2, A. BRYSKIER 3 Abstract E188 ICCAC San Francisco, September 2009

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Microbiological Profile of CAZ104 K. pneumoniae (all strains) European Surveillance 2008 – 2010 (n=1008)

K. pneumoniae (ESBL) European Surveillance 2008 – 2010 (n=205)

MIC50 = <=1 MIC90 = >16 MIC50 = 0.12

MIC90 = 0.5

MIC50 = >16 MIC90 = >16

MIC50 = 0.5 MIC90 = 2

CA-SFM / EUCAST Salmonella

1.  There is clinical evidence for ciprofloxacin to indicate a poor response in systemic infections caused by Salmonella spp. with low-level fluoroquinolone resistance (MIC>0.06 mg/L). The available data relate mainly to S. typhi but there are also case reports of poor response with other Salmonella species.

2.  A. Tests with a ciprofloxacin 5 µg disk will not reliably detect low-level resistance in Salmonella spp. To screen for fluoroquinolone resistance in Salmonella spp., use the pefloxacin 5 µg disk. See Note B.

Pas de diamètre critique pour cipro et salmonelle

1.  Note B: Susceptibility of Salmonella spp. to ciprofloxacin can be inferred from the pefloxacin disk diffusion susceptibility test result.

2.  Pefloxacin screen test 5µg 24 mm

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Staphylocoque doré

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OX SXT KAN GEN

PEF C FOS CTX

TEC RA VAN AMX

PT E P TE

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Entérocoques

Entérocoques

Entérocoques

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pneumocoques

pneumocoques

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Ceftaroline

•  5/B. Methicillin-susceptible isolates can be reported susceptible to ceftaroline without further testing.

•  For methicillin-resistant isolates with ceftaroline zone diameters 17-19 mm, an MIC can be performed to confirm the susceptibility.

0

5

10

15

20

25

30

35

40

45

50

6 8 10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

No

of is

olat

es


Ceftaroline 5 µg vs. MIC MRSA, 70 isolates tested x 4

8

4

2

1

0.5

0.25

0.12

Results from LSI/EUCAST study

MIC breakpoints S ≤ 1 mg/L ≥ 20mm R > 1 mg/L

17-19mm

0

2

4

6

8

10

12

14

16

18

20

6 8 10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

No

of is

olat

es


Enterobacteriaceae vs. ceftaroline 5 µg (Oxoid) 184 clinical isolates, EUCAST BD MH

≥64

32

16

8

4

2

1

0.5

0.25

0.12

0.06

0.03

0.015

0.008

22-24 Clinical breakpoint 0.5 mg/l S≤ 23mm

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Conclusions

•  A tentative zone diameter breakpoint will be set at S ≥ 23 mm, R < 23 mm and will be included in the EUCAST Clinical Breakpoint Table v 3.0.

•  MICs for isolates with zone diameters 22-24 mm should be repeated to validate the tentative breakpoints.

CA-SFM / EUCAST

InfluenceofCa(ons

•  Concentrations of Ca++ and Mg++ known to abolish polymyxin B are about twice that stipulated in the ISO standard

•  Chen & Feingold 1972; ISO 16782

•  No information on the effect of iron, zinc or manganese, which vary between manufacturers/lots of Cation-adjusted Mueller-Hinton broth

•  Girardello et al., 2012

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PolymyxinsinAgar•  Experiences with disk diffusion

»  Polymyxins known for decades to diffuse poorly in agar ( due to charge and/or size?)

»  Poor correlation between zone diameters and BMD MICs

•  e.g. Gales et al., 2001

PolymyxinsinAgar•  Experiences with disk diffusion

»  Some more positive recent experience but still problems with false susceptibility

•  Maalej et al., 2011

PolymyxinsinAgar•  Experiences with the use of Etest®

»  Results not equivalent to broth microdilution •  Van der Heijden et al., 2007

»  Lat et al., 2011 •  2% very major and 23% major errors compared to BMD

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BindingtoPlas(cs

•  Polymyxins are polycationic in solution and will adhere to surfaces with net positive surface charge

OverallSummary•  Problems with broth microdilution

»  Adherence to plastics •  Resolution: stick with current MIC assay method OR add

polysorbate 80?? »  Consequences for work already published and potential to cause

great confusion (and there’s enough already)

•  Problems with Etest and similar on agar »  Poor correlation with BMD

•  Resolution: ??

•  Problems with disk diffusion »  Unacceptable rates of false susceptibility

•  Resolution: ??

Revision of the Telavancin MIC Method and Clinical Breakpoints

Vibativ

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Right Drug Right Patient Right Time © Copyright Clinigen Group plc. All rights reserved

MethodsRevisions:RecommendaZons

§  Op(mizedthesolventanddiluentforBMDtestpanelproduc(on

§  Revisionofstocksolu(on&diluentprepara(on:•  Currentmethod:StockpreparedinDMSOat4mg/mL&dilutedinwater•  Revisedmethod:StockpreparedinDMSOat1.6mg/mL&dilutedinDMSOat100xdesiredfinalconcentra(on

§  Assessedtheeffectofthesurfactantpolysorbate80(P-80;Tween)onMICvalues

§  RevisionofMICTestMethod§  Currentmethod:DilutedirectlyintoMuellerHintonBroth(MHB)§  Revisedmethod:Dilute1:100intoMHB+0.002%P-80

§  Ini(alstudiesindicateda2-4dilu(ondownwardshiginMICswithrevisedmethodology

©2013Theravance,Inc.Allrightsreserved Confiden(al–PropertyofTheravance,Inc.


ComparisonofHABP/VABPPh3clinicalisolateMICswithcurrentandrevisedBMDmethodology

JMIStudy11-THE-01:Ac(vityofTLVagainstbaselineGram-posi(veisolatesfromPh3clinicalstudies

Revisedmethod

Currentmethod



Conclusions

§ ProposedMethodsRevisions:§  Revisedmethod:StockpreparedinDMSOat1.6mg/mL&

dilutedinDMSOat100xdesiredfinalconcentra(on§  Revisedmethod:Dilute1:100intoMHB+0.002%P-80

§  ProposedBreakpointRecommenda(ons:§  S.aureusS≥0.12µg/mL;NS>0.12µg/mL


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SENTRY2011SurveillanceResultswithRevisedBMDmethodology§  2011SurveillancestudyshowsMICrangeof≤0.015to0.25μg/mL

(MIC50/90,0.03/0.06μg/mL)forS.aureus

•  Only1isolateat0.25μg/mL

Organism/groups Resistant subsets (number tested)

MIC(µg/mL) Number (cumulative %) of isolates inhibited at each telavancin MIC (µg/mL)

50% 90% ≤0.015 0.03 0.06 0.12 0.25 0.5

Staphylococcus aureus (5743) 0.03 0.06 170 (3.0) 2917 (53.8) 2633 (99.6) 22 (100.0) 1(100.0)

Oxacillin-susceptible (3386) 0.03 0.06 119 (3.5) 1780 (56.1) 1473 (99.6) 13 (100.0) 1(100.0)

Oxacillin-resistant (2357) 0.03 0.06 51 (2.2) 1137 (50.4) 1160 (99.6) 9 (100.0) --

CoNS3 (739) 0.06 0.06 136 (18.4) 205 (46.1) 384 (98.1) 12 (99.7) 2(100.0)

Oxacillin-susceptible (191) 0.03 0.06 47 (24.6) 59 (55.5) 82 (98.4) 2 (99.5) 1(100.0)

Oxacillin-resistant (548) 0.06 0.06 89 (16.2) 146 (42.9) 302 (98.0) 10 (99.8) 1 (100.0)

JMIstudy10-AST-01:TLVInterna(onalSurveillanceReport,2011©2013Theravance,Inc.Allrightsreserved Confiden(al–PropertyofTheravance,Inc.

ProposedtherapeuZcindicaZon,posology,andspecificpathogens• Treatmentofcomplicatedskinandsog(ssueinfec(ons(cSSTI)inadults

• 1200mgadministeredasasingledosebyintravenous(IV)infusionover3hours

• Efficacydemonstratedinclinicalstudiesagainstthefollowingpathogensthatweresuscep(bletooritavancininvitro:

•  Staphylococcusaureus•  Streptococcuspyogenes•  Streptococcusagalac2ae•  Streptococcusdysgalac2ae•  Streptococcusanginosusgroup

ORBACTIV

OritavancinMICdistribuZons

* Includes S. anginosus, S. constellatus and S. intermedius 12-TMC-02: JMI SENTRY surveillance of clinical isolates collected between 2010-2012 from the US and Europe

Potentinvitroac2vityagainstcSSTIpathogensinrecentsurveillancestudiesinEuropeandUS

No.(cumulaZve%)ofIsolatesatOritavancinMIC(mg/L)

PathogenorGroup N Source ≤0.008 0.015 0.03 0.06 0.12 0.25 0.5

S.aureus8269 US 236(2.9) 2034(27.5) 3279(67.1) 1970(90.9) 617(98.4) 133(100)

5067 Europe 116(2.3) 1147(24.9) 2157(67.5) 1231(91.8) 351(98.7) 65(100)

S.anginosusgroup*

77 US 66(85.7) 8(96.1) 2(98.7) 1(100)

71 Europe 62(87.3) 4(93) 2(95.8) 2(98.6) 1(100)

S.pyogenes526 US 72(13.7) 116(35.7) 138(62.0) 107(82.3) 61(93.9) 27(99.0) 5(100)

434 Europe 34(7.8) 82(26.7) 110(52.1) 97(74.4) 74(91.5) 36(99.8) 1(100)

S.agalac2ae530 US 15(2.8) 119(25.3) 151(53.8) 127(77.7) 82(93.2) 28(98.5) 8(100)

390 Europe 17(4.4) 51(17.4) 84(39.0) 111(67.4) 72(85.9) 49(98.5) 6(100)

S.dysgalac2ae

6 US 1(16.7) 0(16.7) 1(33.3) 2(66.7) 2(100)

28 Europe 1(3.6) 2(10.7) 3(21.4) 10(57.1) 8(85.7) 4(100)

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ScagergramoforitavancinandvancomycinMICsagainstS.aureus(n=13,336)*

*Strainsisolatedin2010-2012fromUSandEurope;brokenhorizontallinesshowpossibleoritavancinbreakpointshavingacceptable(≥95%)predic(vevalues;solidver(callineisvancomycinbreakpoint

>11

0.50.25 18 172 80.12 103 827 380.06 414 2713 740.03 1 1 1260 4122 52

0.015 6 1317 1841 17≤0.008 8 220 122 2

≤0.12 0.25 0.5 1 2 4 8 16 >16

OritavancinM

IC(µ

g/ml)

VancomycinMIC(µg/ml)

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EUCAST Révolution ou changement - Infectiologie...Structure. § Ceftolozane/tazobactam is a novel 3′-aminopyrazolium cephalosporin and β-lactamase inhibitor combination being developed